Sulfonamides of the formula: ##STR3## having a 1,2-diheteroethylene substituent (i.e., an ethylene group containing heteroatom substituents on 1- and 2-positions) on the pyrimidine ring moiety, such as Bosentan, have a wide variety of biological activities including inhibiting the renin angiotensin system and acting as an endothelin antagonist. These compounds are useful in treatment of a variety of illnesses including cardiovascular disorders such as hypertension, ischemia, vasospasms and angina pectoris.
A current method of preparing ethylene glycol sulfonamide derivatives involves reacting an appropriately substituted pyrimidine monohalide with a monoanion ethylene glycol (e.g., sodium ethylene glycol) typically using ethylene glycol as a solvent. However, one of the disadvantages of using a monoanion of ethylene glycol is the formation of undesired ethylene glycol bis-sulfonamide in which two molecules of the pyrimidine monohalide are coupled with one molecule of ethylene glycol. The formation of this bis-sulfonamide compound requires costly and laborious separation steps to obtain a pharmaceutically suitable pure ethylene glycol sulfonamide compound. In addition, the use of ethylene glycol as a solvent, which is acceptable in a small scale reaction, is impracticable in a large industrial scale synthesis because of its toxicity and its high boiling point which requires a large amount of time and high energy consumption to remove it by distillation.
Another drawback to the current synthesis is the need for isolating a pyrimidine dihalide (W=halide) of the formula: ##STR4## which is believed to be a potent sensitizer. This problem is further complicated by the use of a halogenated solvent, e.g., methylene chloride, during the isolation of pyrimidine dihalide. Halogenated solvent is expensive to dispose of properly, thus leading to an added cost.
Furthermore, the current synthesis requires at least six separate isolation steps and the use of many different solvents, which makes it economically less attractive as an industrial process.
Therefore, there is a need for a process for preparing the above described 1,2-diheteroethylene sulfonamides with a reduced number of reaction product isolation steps. There is a need for a process for preparing the 1,2-diheteroethylene sulfonamides which does not produce undesired 1,2-diheteroethylene bis-sulfonamides. There is a need for a process for preparing the 1,2-diheteroethylene sulfonamides which does not require isolation of potent sensitizers such as pyrimidine dihalide and/or pyrimidine monohalide intermediates.